We are using DNA microarrays to study the Streptomyces bacteria, which have been an extremely rich source of antibiotics and other therapeutics for the pharmaceutical industry. In 1993, the antibiotic production capability of Streptomyces coelicolor was harnessed at Stanford University in the design of a versatile production system for engineered natural products. This production system has since been used to generate over one hundred novel natural product-like molecules, demonstrating new strategies for developing therapeutics against antibiotic-resistant pathogens and other medical diseases. However, many of these molecules are produced in small quantities in vivo, and future challenges are aimed at improving production yields that are commensurate with biological screening assays and commercial distribution. Recently, scientists at KOSAN Biosciences (Hayward, CA) isolated S. coelicolor production strains that generate more than ten-fold greater yields of engineered natural products. Increased production was found to be associated with the presence of abnormally high copy numbers of the production plasmid encoding antibiotic synthesis genes. This phenotype is now being harnessed as a tool by KOSAN to generate other high-producing strains, and the company is attempting to identify the genetic changes that alter copy number regulation. As a collaboration between Dr. Camilla Kao at Stanford University and Dr. C. Richard Hutchinson at KOSAN Biosciences, we are also attempting to understand the metabolic differences between production strains with high and low titers, and which genetic elements in the production plasmids contribute to increased product yields when present at high copy number. Greater understanding of the metabolic and genetic factors that influence natural product production should lead to new multi-pronged strategies for improving Streptomyces and other microbial production systems.